Circadian clocks are important regulators of cellular functions and homeostasis. Age-related alterations in the human circadian system are implicated in neuronal pathologies. Recent evidence in fruit flies and mice suggests a correlation between disrupted rhythms and neurodegeneration; however, very little is known about the mechanisms involved. To address this, we compared the circadian transcriptome in young and old Drosophila heads using RNA- Seq. As expected, we found that several genes that were expressed rhythmically in young flies lose their cycling patterns to become constitutively low or high in old flies. Surprisingly, we also uncovered a novel group of genes which were low and arrhythmic in heads of young flies that became highly expressed and strongly rhythmic in old. This group contains known stress- responsive genes that are induced in response to oxidative stress or hypoxia to protect proteins from damage. Based on our preliminary data, we hypothesize that the circadian system orchestrates rhythmic expression of neuroprotective genes, which we termed late life cyclers (LLCs), in response to intrinsic stress and damage in the aging nervous system. We will test our hypothesis in two Aims. In Aim 1, we will conduct a comprehensive comparison of the circadian transcriptome in the heads of young and old males and females to fully characterize age-related changes in core clock and clock-controlled genes, and determine whether these changes are sexually dimorphic. We will also test whether LLC rhythms are maintained in constant darkness but abolished in flies with clock-disrupting null mutations in core circadian genes. In Aim 2, we will test whether LLCs play neuroprotective roles by comparing biomarkers of aging in wild type and clock mutant flies with LLC rhythms present or absent. We will also test whether exposure to exogenous oxidative stress induces rhythmic LLC expression in young flies. This explorative proposal may reveal clock-controlled pathways that protect the brain from age-related damage. Given the conserved genetic mechanisms of the circadian clock and aging biology, these pathways may also function in mammals.